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OBJECTIVE: Preclinical evidence and early clinical trials have demonstrated the activity of SPL-108, a targeted agent that inhibits CD44 mediated induction of multidrug resistance specifically to paclitaxel and platinum agents. We conducted a phase I, open label, dose escalation study of the safety and tolerability of the combination of SPL-108 with weekly paclitaxel in patients with platinum resistant CD44+ ovarian, primary peritoneal, or fallopian tube cancer. METHODS: Patients with platinum resistant histologically proven epithelial ovarian, primary peritoneal, or fallopian tube cancers and measurable disease according to RECIST (Response Evaluation Criteria in Solid Tumours) version 1.1 were selected. Tumors were tested for CD44 expression for eligibility, defined as strong (+++) or moderate (++) staining in ≥20% of the tumor tissue or diffuse + staining. Patients were treated with daily and then twice daily SPL-108 subcutaneous injections and weekly intravenous paclitaxel on days 1, 8, and 15 of a 28 day cycle. Endpoints included safety, determination of maximum tolerated dose, and efficacy. Tumors underwent comprehensive genomic profiling, and cell lines and western blotting were used to study markers of response. RESULTS: We screened 16 patients, and 14 were enrolled based on CD44+ expression. A total of 86% of patients had high grade serous tumors and all had received multiple prior therapies. There were no grade 4-5 toxicities. One patient had grade 3 peripheral sensory neuropathy attributed to paclitaxel and one patient developed presumed colonic perforation attributed to the study drug. No dose reductions or treatment discontinuations were required. All patients tolerated the maximum planned dose; no maximum tolerated dose was reached. Overall response rate was 36%; 5 (36%) patients had partial response and 5 (36%) patients had stable disease. CONCLUSIONS: The combination of SPL-108 with weekly paclitaxel was safe and well tolerated. Encouraging antitumor activity was observed, with 72% of patients deriving a clinical benefit. TRIAL REGISTRATION: NCT03078400.
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Hyaluronan (HA) is a non-sulfated glycosaminoglycan distributed throughout the extracellular matrix that plays a major role in cell adhesion, migration, and proliferation. CD44, a multifunctional cell surface glycoprotein, is a receptor for HA. In addition, CD44 is known to interact with other receptors and ligands, and to mediate a number of cellular functions as well as disease progression. Studies have shown that binding of HA to CD44 in cancer cells activates survival pathways resulting in cancer cell survival. This effect can be blocked by anti-CD44 monoclonal antibodies. A6 is a capped, eight l-amino acid peptide (Ac-KPSSPPEE-NH2) derived from the biologically active connecting peptide domain of the serine protease, human urokinase plasminogen activator (uPA). A6 neither binds to the uPA receptor (uPAR) nor interferes with uPA/uPAR binding. A6 binds to CD44 resulting in the inhibition of migration, invasion, and metastasis of tumor cells, and the modulation of CD44-mediated cell signaling. A6 has been shown to have no dose-limiting toxicity in animal studies. A6 has demonstrated efficacy and an excellent safety profile in Phase 1a, 1b, and 2 clinical trials. In animal models, A6 has also exhibited promising results for the treatment of diabetic retinopathy and wet age-related macular degeneration through the reduction of retinal vascular permeability and inhibition of choroidal neovascularization, respectively. Recently, A6 has been shown to be directly cytotoxic for B-lymphocytes obtained from patients with chronic lymphocytic leukemia expressing the kinase, ZAP-70. This review will discuss the activity of A6, A6 modulation of HA and CD44, and a novel strategy for therapeutic intervention in disease.
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The A6 peptide (acetyl-KPSSPPEE-amino) has antitumor activity in the absence of significant adverse events in murine tumor models and clinical trials. A6 shares sequence homology with CD44, an adhesion receptor involved in metastasis that is also a marker of cancer stem cells and drug-resistant phenotypes. We investigated the mechanism of action of A6 by examining its effects on CD44 activity, cell migration, and metastasis. A6 inhibited the migration of a subset of ovarian and breast cancer cell lines, exhibiting IC(50) values of 5 to 110 nmol/L. The ability of A6 to inhibit migration in vitro correlated with CD44 expression. Immunopreciptation studies showed that CD44 binds A6 and that biotin-tagged A6 can be cross-linked to CD44. The binding of A6 altered the structure of CD44 such that it was no longer recognized by a monoclonal antibody to a specific epitope. Importantly, A6 potentiated the CD44-dependent adhesion of cancer cells to hyaluronic acid and activated CD44-mediated signaling, as evidenced by focal adhesion kinase and MAP/ERK kinase phosphorylation. In vivo, A6 (100 mg/kg delivered s.c. twice daily) reduced the number of lung foci generated by the i.v. injection of B16-F10 melanoma cells by 50% (P = 0.029 in an unpaired t test). We conclude that A6 potently blocks the migration of CD44-positive cells in vitro through an interaction with CD44 that alters its structure and activates CD44 to enhance ligand binding and downstream signaling. The concurrent ability of A6 to agonize the CD44 receptor suggests that CD44 activation may represent a novel strategy for inhibiting metastatic disease.